toxins Review Long-Term Effects of Snake Envenoming Subodha Waiddyanatha 1,2, Anjana Silva 1,2 , Sisira Siribaddana 1 and Geoffrey K. Isbister 2,3,* 1 Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Saliyapura 50008, Sri Lanka; [email protected] (S.W.); [email protected] (A.S.); [email protected] (S.S.) 2 South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya 20400, Sri Lanka 3 Clinical Toxicology Research Group, University of Newcastle, Callaghan, NSW 2308, Australia * Correspondence: [email protected] or [email protected]; Tel.: +612-4921-1211 Received: 14 March 2019; Accepted: 29 March 2019; Published: 31 March 2019 Abstract: Long-term effects of envenoming compromise the quality of life of the survivors of snakebite. We searched MEDLINE (from 1946) and EMBASE (from 1947) until October 2018 for clinical literature on the long-term effects of snake envenoming using different combinations of search terms. We classified conditions that last or appear more than six weeks following envenoming as long term or delayed effects of envenoming. Of 257 records identified, 51 articles describe the long-term effects of snake envenoming and were reviewed. Disability due to amputations, deformities, contracture formation, and chronic ulceration, rarely with malignant change, have resulted from local necrosis due to bites mainly from African and Asian cobras, and Central and South American Pit-vipers. Progression of acute kidney injury into chronic renal failure in Russell’s viper bites has been reported in several studies from India and Sri Lanka. Neuromuscular toxicity does not appear to result in long-term effects. Endocrine anomalies such as delayed manifestation of hypopituitarism following Russell’s viper bites have been reported. Delayed psychological effects such as depressive symptoms, post-traumatic stress disorder and somatisation have been reported. Blindness due to primary and secondary effects of venom is a serious, debilitating effect. In general, the available studies have linked a clinical effect to a snakebite in retrospect, hence lacked accurate snake authentication, details of acute management and baseline data and are unable to provide a detailed picture of clinical epidemiology of the long-term effects of envenoming. In the future, it will be important to follow cohorts of snakebite patients for a longer period of time to understand the true prevalence, severity, clinical progression and risk factors of long-term effects of snake envenoming. Keywords: long-term; chronic; delayed; envenoming; snakebite Key Contribution: The present review highlights the lack of authenticated data on the long-term effects of snake envenoming globally. We highlight the need for long-term follow-up of snakebite cohorts to understand the true burden and the clinical epidemiology of long-term effects of snake envenoming. 1. Introduction Snakebite is a neglected tropical disease that mainly affects poor farming communities in the rural tropics [1]. Snake envenoming is often under-reported, and there is limited accurate data on the global burden of snakebites. The high estimates suggest that there are 5.5 million bites, 1.8 million envenomings and 94,000 deaths annually due to snakebite [2]. The largest burden of snakebite occurs in South Asia, Southeast Asia, Sub-Saharan Africa and Latin America. Toxins 2019, 11, 193; doi:10.3390/toxins11040193 www.mdpi.com/journal/toxins Toxins 2019, 11, 193 2 of 13 Snake envenoming can cause acute local and systemic effects due to the actions of toxic components in the venom. Some elapid and viperid snakes cause tissue injury at the bite site, manifesting initially with oedema, pain, redness and blistering. In more severe cases, there may be subsequent dermonecrosis and myonecrosis, occasionally requiring debridement and rarely amputation. The commonest important systemic manifestations of snake envenoming are venom induced consumption coagulopathy, neuromuscular paralysis, acute kidney injury, myotoxicity and cardiovascular collapse [3–6]. Initial treatment is with antivenom and supportive care, depending on the specific clinical effects. The vast majority of patients are then discharged once these effects have resolved. Occasionally patients with complications require a more prolonged hospital stay. Most snakebite patients are not followed up once they are discharged from hospital and the acute effects have resolved. They rarely have further contact with the healthcare system in relation to the snakebite. Although some acute pathological effects of envenoming might completely resolve within a few days of the bite, other pathological effects or their consequences may last for months or years [7–10]. However, due to the lack of follow up clinically and in research studies, the long-term effects of snake envenoming are poorly defined. In addition, some effects, such as the psychological effects resulting from the snakebite, are likely to have a delayed onset [11]. In this review, we aim to summarise our current knowledge of the long-term effects of snake envenoming and identify the knowledge gaps. 2. Long-term Sequalae of Local Effects 2.1. Local Necrosis Resulting in Amputation Most viperid and some elapid envenomings cause local tissue injury. Occasionally, this is more severe with varying degrees of necrosis of the skin, subcutaneous tissues and muscles [12,13]. In addition to the toxin mediated tissue necrosis, rapidly developing oedema can lead to a compartment syndrome, which can result in limb ischaemia [14]. Secondary infections at the bite site can further aggravate the tissue injury and prolong the recovery [15]. The above conditions usually require surgical management. Uncommonly, partial amputation of the limb at different levels and/or digits is required in order to stop further spread of tissue injury [16]. Even if amputation is not required, tissue loss resulting from necrosis, subsequent fibrosis and formation of contractures of various tissues can lead to impaired or loss of function in limbs. Detailed descriptions of the long-term sequalae of the local effects of authenticated snake envenoming are rare. In particular, literature on the long-term socioeconomic burden following amputations due to snake envenoming is scarce. Several studies report the acute stages of snakebites that result in amputation. This provides some insight into their long-term impact. In a study from Nigeria, of 16 snakebite patients who presented late and lost an upper or lower limb due to amputation, the median age was 12 years (2–55). This demonstrates the duration of the disability in the survivors, being so young at the time of the bite [16]. Cobras [13,16–19], true vipers and pit-vipers [20–25] are reported most commonly to cause extensive local tissue injuries. In a recent population-based cross-sectional study from Sri Lanka, of 816 snakebite victims, 26 (3.2%) had a range of musculoskeletal disabilities that persisted for an average period of 13.4 years [9]. Despite the limitations of a population-based study, in which case-authentication is lacking, the study reported a range of long-term disabilities due to local envenoming following snakebite. These included contractures and deformities, muscle wasting, joint stiffness, reduced range of movement and impaired balance. Some of these effects, such as reduced range of movements are mostly reported in those who did not undergo an exercise program to improve the range of motions, hence likely preventable [9]. 2.2. Chronic Ulcers Another important local injury is the development of a chronic ulcer at the bite site. This can cause extensive scarring followed by transformation into squamous cell carcinoma, similar to a Marjolin Toxins 2019, 11, 193 3 of 13 ulcer. Chronic ulcers have been reported in a possible pit-viper bite in Brazil [26] and a black-necked spitting cobra (Naja nigricollis) bite [27]. These consequences are extremely rare, but can result in severeToxins 2019 morbidity., 11, x FOR PEER REVIEW 3 of 13 2.3. Chronic Local Pain and Swelling Less severe effects of local envenoming have also been reported for some snakes. In a follow-up telephone survey survey conducted conducted in inCalifornia, California, 6 of 6the of 13 the patients 13 patients with rattlesnake with rattlesnake bites reported bites reportedlocalised localisedpain, numbness pain, numbness or paraesthesia, or paraesthesia, abnormal abnormal skin peeling skin peelingand discolouration and discolouration at the atbite the site, bite with site, withpersistent persistent weakness weakness of the of bitten the bitten extremity extremity for for7 months 7 months to to12 12 years years [28]. [28]. Similar Similar effects effects were experienced for weeks to months after the bite by snakebite survivors in Sri Lanka [[10].10]. Complex regional pain syndrome has been reported following viper bites from South Korea, Turkey and Norway [29[29–31].–31]. This This symptom symptom complex complex lasts overlasts sixover weeks six and weeks includes and allodynia includes and allodynia hyperalgesia, and inhyperalgesia, addition to in pain addition at the biteto pain site. at The the burdenbite site. of The persistent burden localof persistent pain and local its impact pain and on its the impact post-bite on qualitythe post-bite of life quality requires of furtherlife requires investigation, further investigation, as it is likely as that it is many likely snakebite that